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  • Investigation of Powassan virus lineage II pathogenesis and neurotropism in mice
    by Courtney, S. J., Gallichotte, E., Nilsson, E., Trammell, C., Kimball, K., Fagre, A., Vilander, A., Overby, A. K., Ebel, G. D.
    Powassan virus (POWV) is an emerging tick-borne flavivirus that causes disease in humans. POWV has considerable genetic and phenotypic diversity, including highly variable replication in vitro and pathogenesis in mice. This study sought to define the extent of variability in pathogenesis within POWV lineage II in mice and investigate possible viral determinants. Relative to other strains, two New York-derived isolates, NY.19.12 and NY.19.32, caused earlier clinical signs and earlier detection of viral RNA (vRNA) in the spleen and brain compared […]
  • HeartMap: An Integrated Cell Atlas of 2.4 million cells across 209 Individuals in Health and Disease
    by Datar, Y., Chaffin, M., Simonson, B., Mandia, A., Ellinor, P. T.
    Cardiovascular disease remains the leading cause of global mortality. Understanding its complexity requires dissecting the heart's cellular landscape. We present HeartMap, a comprehensive single-nucleus RNA sequencing atlas of the adult human heart. This resource integrates data from nine studies, encompassing over 2.4 million nuclei, 209 individuals, eight anatomical regions, and seven disease and healthy states. After rigorous data harmonization and benchmarking of batch-correction methods, we characterized transcriptional diversity across 14 cell types. To demonstrate the utility of HeartMap, we identified […]
  • Splicing of a core clock gene regulates seasonal adaptations by a winter gating mechanism
    by Hidalgo, S., Del Rio, R., Tabuloc, C. A., Perez Hernandez, L. A., Berry, A. L., Cai, Y. D., Lewald, K. M., Chiu, J. C.
    Seasons bring changes to the environment. Many organisms adjust their physiology and behavior in response to seasonal changes in order to survive. Although the molecular mechanisms mediating the integration of seasonal cues are still unclear, the working model indicates the involvement of the circadian clock. Notably, the circadian neuropeptide Pigment Dispersing Factor (PDF), an output of the circadian clock, has been shown to alter its expression and activity in response to seasonal changes to facilitate seasonal adaptations in insects. Here, […]
  • Automated spermatogenic staging in PAS-stained testes of Sprague-Dawley rats using a deep learning model for nomal and atrophied tissues
    by Kim, D.-M., Rho, J.-H., Wee, S.-Y., Son, H.-Y.
    The spermatogenic stage serves as a vital criterion for assessing normal spermatogenesis and is central to evaluating reproductive toxicity. Current manual methods for spermatogenic stage evaluation are time-intensive, require expert knowledge, and are less effective in detecting subtle changes or comparing stage frequencies across samples. To overcome these limitations, this study introduces a method leveraging the object detection models, Region-based Convolutional Neural Networks (R-CNN), for efficient and accurate spermatogenic stage evaluation. 14 stages were identified using Periodic Acid-Schiff (PAS)-stained Sprague-Dawley […]
  • SPARK: in silico simulations for benchmarking nascent RNA sequencing experiments
    by Calvo-Roitberg, E., Lehman, J. W., Tam, E., Elhajjajy, S., Engelhardt, B. E., Pai, A. A.
    Nascent RNA sequencing offers profound insights into transcriptional dynamics, yet there are substantial challenges to analyzing these data. The development of proper computational tools necessitates realistic benchmarking datasets that reflect biological variability and technical biases. We present simulated pre-mRNA and RNA kinetics (SPARK), a versatile in silico framework for generating reads across nascent RNA sequencing approaches. SPARK simulates the process of transcription – allowing for variable elongation rates and pausing events – and key experimental features. SPARK provides a comprehensive […]
  • Morphological Identification of Ticks in district Swabi, Mardan, and Charsadda
    by Mohammad, A., Hongsu, H., Ali, A., Zhao, J., Wu, Y., Alam, U., Dai, J., Zhao, C., Zhao, T., Hui, Z., Zhihua, S.
    Ticks are ectoparasitic arthropods that play a significant role in transmitting pathogens to humans and animals. This study aimed to address the research gap in understanding the morphological diversity and distribution of tick species in Swabi, Mardan, and Charsadda districts of Pakistan, where tick-borne diseases are prevalent but poorly documented. The primary objectives were to identify tick species, document their morphological characteristics, and map their distribution patterns across different habitats. Field surveys were conducted over nine months, collecting tick specimens […]
  • A 5'-end based Molecular Marker Enables Identification and Deployment of a Functional Rpi-vnt1.1 Allele for Durable Late Blight Resistance in Potato
    by Wang, S., Wang, L., Feng, S., Hu, C., Meng, X., Chang, S., Feng, Y., Kong, L., Zhao, X.
    Potato (Solanum tuberosum) is a globally important food crop, yet its production is severely threatened by late blight, caused by Phytophthora infestans. Deploying resistance (R) genes in breeding programs offers a sustainable approach for disease management. Rpi-vnt1.1 is a broad-spectrum R gene cloned from wild Solanum species Solanum venturii. Here, we developed a PCR marker targeting the 5'-end extension of Rpi-vnt1.1, which enables efficient and specific detection of the resistant alleles. Screening of advanced breeding lines from the International Potato […]
  • Conjugates of α-d-Galp-(1->3)-β-d-Galp for the serological diagnosis of Chagas disease.
    by Balouz, V., Lopez, R., Conte, N., Abal, M., Ducrey, I., Giorgi, M. E., de Lederkremer, R. M., Altcheh, J., Ciocchini, A. E., Melli, L. J., Marino, C., Buscaglia, C. A.
    Background: Chagas disease (ChD), caused by the parasitic protozoan Trypanosoma cruzi, is a lifelong, neglected tropical disease with substantial medical and socioeconomic impact. Despite this situation, currently available diagnostic and therapeutic methods display serious limitations. A promising strategy to improve ChD serodiagnosis involves targeting parasite carbohydrate antigens, particularly the -galactosyl-rich mucins that coat the surface of bloodstream trypomastigotes (tGPI-mucins). Methods/Principle Findings: Here, we present a concise and efficient protocol for the chemical synthesis of a tGPI-mucin-derived glycotope, the disaccharide -d-Galp-(1[->]3)-{beta}-d-Galp, […]
  • Daily Heat Stress Induces Accumulation of Non-functional PSII-LHCII and Donor-side Limitation of PSI via Downregulation of the Cyt bf Complex in Arabidopsis thaliana
    by Laihonen, L., Tomberg, T., Vuorijoki, L., Mulo, P., Rantala, M.
    Ongoing climate change has intensified heatwaves, which suppress photosynthesis and thus threatens agriculture. While acute heat stress damages photosystem II (PSII), detach light harvesting complex (LHC)II from PSII core and linearize thylakoid membrane, the consequences of prolonged recurring moderate heat exposure across the plant life cycle remain unclear. Here we characterized the effects of long-term daily exposure to high temperature on thylakoid membrane ultrastructure, photosynthetic protein complexes and their function, as well as to the redox states of PSI electron […]
  • Drosophila ryanodine receptor gene triggers functional and developmental muscle properties and could be used to assess the impact of human RYR1 mutations
    by Jagla, K., Zmojdzian, M., Teresa, J., Cherik, F., Dubinska-Magiera, M., Migocka-Patrzalek, M., Daczewska, M., Rendu, J., Sarret, C.
    The ryanodine receptor (RYR) genes encode evolutionarily conserved calcium release channels involved in a wide range of calcium-dependent biological processes. Here we show that the sole Drosophila RYR gene (dRyR) functions in differentiated somatic and cardiac muscle as well as in developing embryonic myotubes. In the larval body wall muscles, dRyR protein localizes at the SR membranes and dRyR knockdown adversely affects muscle contractility, suggesting its conserved role in calcium-triggered E C coupling. After dRyR attenuation, sarcomere and mitochondrial patterns […]
  • Secondary bile acid lithocholic acid ameliorates colitis-like inflammation in a human intestine-on-chip system
    by Kaden, T., Allwang, M., Stallhofer, J., Graf, K., Raasch, M., Mosig, A. S.
    Inflammatory bowel disease (IBD) is a multifactorial disease of the gastrointestinal tract without curative treatment. Previous studies highlighted that altered fecal bile acid levels correlate with intestinal microbiota composition changes and inflammation in IBD. Lithocholic acid (LCA) is a secondary bile acid (SBA) drastically reduced during active IBD but mediates beneficial effects at the mucosal intestinal barrier during intestinal homeostasis. In a dextran sodium sulfate (DSS)-induced colitis-on-chip model, it was investigated whether the administration of LCA has a protective impact […]
  • The Bone Morphogenetic Pathway Controls the Uptake of Infectious Prions
    by De Cecco, E., Mariutti, G., Oueslati Morales, C. O., Caredio, D., Erana, H., Appleton, C., Sellitto, S., Hornemann, S., Scialo, C., Yin, J.-A., Vidal, E., Polymenidou, M., Castilla, J., Aguzzi, A.
    Prion diseases are transmissible neurodegenerative disorders caused by the spread of misfolded prion protein between cells and individuals, yet the paths by which prions colonize cells are undefined. Here we map the determinants of prion uptake with a genome-wide quadruple-guide CRISPR activation screen. Uptake of prions was measured by flow cytometry in PRNP-ablated human SHSY-5Y cells exposed to synthetic ovine prions. We identified 43 genes modulating prion uptake, 6 of which belonged to the core components of the Bone Morphogenetic […]
  • Modeling Phage Therapy
    by De Boer, R. j., Schooley, R., Perelson, A. S.
    Patients infected with life-threatening multi-drug resistant (MDR) bacteria have been treated with cocktails of bacteriophages. This is a complicated form of personalized medicine as the phages given to a patient have to be selected beforehand on the basis of their lytic capacity of the infecting bacteria. Because bacteria rapidly become resistant, the evolution of resistance to a diverse cocktail of phages is a complicated dynamical process, during which competing bacterial strains replace one another by accumulating several resistance mechanisms, each […]
  • Influence of iron uptake systems on cefiderocol activity in Escherichia coli: at the crossroads of antibiotic resistance and virulence
    by Mallecot, E., Berti, V., Petitjean, M., MEYER, J., Gueye, S., Morel-Journel, T., Clermont, O., Poirel, L., Denamur, E., Royer, G., Armand, L.
    Cefiderocol (FDC) is a new siderophore-conjugated cephalosporin that enters the periplasm via iron transport systems. However, the specific contribution of individual iron uptake pathways to FDC activity remains unclear. We investigated the role of 12 iron acquisition systems using several Escherichia coli strain collections. FDC MICs were determined in iron-depleted and iron-supplemented media for E. coli mutants (Keio and pathogenic island [PAI]-deleted collections) and for clinical wild-type or TEM-producing E. coli (WT/TEM-Ec) and NDM-producing (NDM-Ec) isolates. The distribution of iron […]
  • Repeated fentanyl abstinence intensifies opioid withdrawal and induces a proinflammatory state in striatal microglia
    by Bergkamp, D. J., Coffey, K. R., Dawkins, A. J., Rice, M. T., Peden-Asarch, A. M., Neumaier, J. F.
    Opioid withdrawal is a serious obstacle to self-initiated abstinence, and previous experiences of opioid withdrawal may exacerbate the severity of subsequent incidences. To study the impact of repeated opioid withdrawal episodes, we compared male and female mice after one or five cycles of fentanyl exposure and withdrawal. We selectively expressed hemagglutinin-tagged ribosomes (RiboTag) in microglia of transgenic mice to immunoprecipitate and sequence RNA actively undergoing translation (the 'translatome') from striatal microglia during fentanyl withdrawal. Key changes were confirmed by RTqPCR […]
  • Characterization of an Open-Channel Structure and Lateral Conduction Pathway in the Cation-Selective Pentameric Ligand-Gated Ion Channel, ELIC
    by Arcario, M. J., Wu-Chen, E. J., Henin, J., Brannigan, G., Cheng, W. W.-L.
    Open-channel structures have been determined of multiple pentameric ligand-gated ion channels (pLGIC), including the prokaryotic model pLGIC, ELIC (Erwinia ligand-gated ion channel). For many of these structures, it remains uncertain whether they represent the physiologic open-channel state because the conditions used for structure determination do not match those of functional measurements in cell membranes. Here, molecular dynamics (MD) simulation is used to examine the ion conduction properties of the ELIC open-channel structure, which was determined using a non-desensitizing mutant called […]
  • Patient-Specific Midbrain Organoids with CRISPR Correction Reveal Disease Mechanisms and Enable Therapeutic Evaluation in Neuronopathic Gaucher Disease
    by Lin, Y., Liou, B., Fannin, V., Adler, S., Mayhew, C. N., Hammonds, J. E., Hu, Y.-C., Tchieu, J., Zhang, W., Zhao, X., Beres, R. L., Setchell, K. D., Kaynak, A., Qi, X., Feldman, R. A., Sun, Y.
    Neuronopathic Gaucher disease (nGD) is a lysosomal storage disorder caused by GBA1 mutations, leading to defective acid {beta}-glucosidase (GCase) and accumulation of glycosphingolipid substrates, causing inflammation and neurodegeneration. Patients with nGD manifests severe neurological symptoms, but current animal models fail to fully recapitulate human condition, posing a major barrier to the development of effective therapies targeting the brain. To bridge this gap, we have developed midbrain-like organoids (MLOs) from human induced pluripotent stem cells (hiPSCs) of nGD patients with GBA1L444P/P415R […]
  • Multi-Dimensional Spatiotemporal Attention Neural Network for Next Generation Sequencing Basecalling
    by Peng, K., Chen, W., Yao, T., Xia, H., Fu, G., Li, G., Bao, Y., Liu, E., Zhao, L., Wang, G.
    Next-generation sequencing (NGS) remains the most used sequencing technique in the field of genomics. Traditional basecall methods face significant challenges in decoding high density sequencing data due to inherent noise in biochemical reactions and limitations of instruments. Here, we present a multi-dimensional deep learning neural network based on spatiotemporal attention mechanism named AICall. The network skips computationally heavy but less effective steps of peak finding and brightness extraction/correction, and directly basecalls from the time sequence of multi-dimensional image stacks obtained […]
  • Barley (Hordeum vulgare) maintains tricarboxylic acid cycle activity without invoking the GABA shunt under salt stress
    by Bandehagh, A., Taylor, N. L.
    Plants maintain energy balance under salinity stress through increased respiration and energy use, processes also associated with reactive oxygen species generation. Although respiration imposes a high energy cost, mitochondrial respiration and the tricarboxylic acid (TCA) cycle activity are vital for ATP production and providing electron donors that drive ion exclusion and ROS detoxification. This study examined the molecular basis of respiratory responses to salinity in barley using physiological, biochemical, metabolomic, and proteomic analyses. Salt exposure resulted in sodium accumulation, decreased […]
  • High dynamic range shortwave infrared (SWIR) imaging of mice with an InGaAs camera
    by Patel, A., Zhong, X., Moffett, M. A., Sun, Y., Dennis, A. M.
    Significance: While shortwave infrared (SWIR) imaging provides superior tissue penetration and reduced autofluorescence for preclinical applications, quantitative fluorescence analysis is hindered by the limited dynamic range of InGaAs cameras, forcing a focus on either bright or dim anatomical features. Aim: We develop a high dynamic range (HDR) imaging method specifically adapted for the high-noise characteristics of InGaAs detectors to enable quantitative fluorescence imaging across wide intensity ranges. We demonstrate that one-time camera calibration based on a series of images encompassing […]

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